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Cardiovascular Research 2006 71(3):430-442; doi:10.1016/j.cardiores.2006.04.012
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Copyright © 2006, European Society of Cardiology

Molecular aspects of adrenergic modulation of the transient outward current

Marcel A.G. van der Heydena,*, Tessa J.M. Wijnhovena and Tobias Opthofa,b

aDepartment of Medical Physiology, University Medical Center Utrecht, The Netherlands
bExperimental and Molecular Cardiology Groups, Academic Medical Center, Amsterdam, The Netherlands

* Corresponding author. Department of Medical Physiology, University Medical Center Utrecht, Yalelaan 50, 3584 CM Utrecht, The Netherlands. Tel.: +31 30 2538900; fax: +31 30 2539036. Email address: m.a.g.vanderheyden{at}med.uu.nl

Transient outward channels have a different impact on action potential configuration in small mammals compared to large mammals. Small mammals depend primarily on Ito1 for repolarization, while in larger animals Ito1 only indirectly determines action potential duration by setting the level of the plateau. Transient outward channel expression and distribution also differ between animal species. Nevertheless, the primary protein sequence of the underlying Kv1.4, Kv4.2 and Kv4.3 {alpha}1-subunits displays remarkably high levels of amino acid identity. Transient outward channels are subject to {alpha}- and β-adrenergic regulation, mainly decreasing Ito1. However, adrenergic stimulation is also an important determinant of transient outward channel downregulation in cardiac disease. Adrenergic stimulation of PKA as well as PKC leads to an inhibition of Ito1, which has been correlated with phosphorylation of the Kv1.4, Kv4.2 and Kv4.3 {alpha}1-subunits. Calmodulin-dependent kinase II, on the other hand, has been shown to be involved in an increase of Ito1. Comparison of Kv1.4, Kv4.2 and Kv4.3 primary amino acid sequences demonstrates a strong conservation of (potential) phosphorylation sites between different species, despite the fact that Ito1 has a different effect on action potential configuration in mammalian species.

KEYWORDS Action potentials; Adrenergic (ant) agonists; G-proteins; Phosphorylation; Protein kinase A; Protein kinase C; Tyrosine protein kinase; Transient outward current

Abbreviations: AKAP, A-kinase anchoring protein • AR, adrenergic receptor • AC, adenylate cyclase • ATP, adenosine trisphosphate • CaMKII, Ca2+ calmodulin-dependent kinase II • cAMP, cyclic adenosine monophosphate • cGMP, cyclic guanosine monophosphate • DAG, 1,2-diacylglycerol • ERK, extracellular-signal-regulated kinase • G protein, guanosine 5'-triphosphate (GTP)-binding protein • ICa-L, L-type Ca2+ current • Ito1, transient outward current • InsP3, inositol 1,4,5-trisphosphate • PIP2, phosphatidylinositol 4,5-bisphosphate • PK, protein kinase • PLC, phospholipase C • PTK, protein tyrosine kinase • Ser, serine • Thr, threonine • Tyr, tyrosine

Time for primary review 19 days


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